FLUOROURACIL: 53,045 Adverse Event Reports & Safety Profile

Fluorouracil injection, USP, a nucleoside metabolic inhibitor, is a colorless to yellow aqueous, sterile, nonpyrogenic injectable solution available in a pharmacy bulk package, a sterile preparation that contains doses for multiple patients for intravenous administration. Each mL contains 50 mg fluorouracil in water for injection, USP. The pH is adjusted to approximately 9.2 with sodium hydroxide. Chemically, fluorouracil, a fluorinated pyrimidine, is 5-fluoro-2,4 (1 H ,3 H )-pyrimidinedione. Its structural formula is: C 4 H 3 FN 2 O 2 M.W. 130.08 A pharmacy bulk package is a container of a sterile preparation for parenteral use that contains many single doses. The contents are intended for use in a pharmacy admixture program and are restricted to the preparation of admixtures for intravenous infusion or the filling of empty sterile syringes for patients with individualized dosing requirements. fluor-struc-01.jpg

INDICATIONS AND USAGE: Fluorouracil is recommended for the topical treatment of multiple actinic or solar keratoses. In the 5% strength, it is also useful in the treatment of superficial basal cell carcinomas when conventional methods are impractical, such as with multiple lesions or difficult treatment sites. Safety and efficacy in other indications have not been established. The diagnosis should be established prior to treatment, since this method has not been proven effective in other types of basal cell carcinomas. With isolated, easily accessible basal cell carcinomas, surgery is preferred since success with such lesions is almost 100%. The success rate with fluorouracil solution and a different dosage form is approximately 93%, based on 113 lesions in 54 patients. Twenty-five lesions treated with the solution produced 1 failure and 88 lesions treated with a different dosage form produced 7 failures.

AND ADMINISTRATION Fluorouracil is recommended for administration either as an intravenous bolus or as an intravenous infusion. ( 2.1 )

See Full Prescribing

Information for dose individualization (2.1) and dose modifications due to adverse reactions (2.6)

See Full Prescribing

Information for recommended doses of fluorouracil for adenocarcinoma of the colon and rectum (2.2) and for recommended doses of fluorouracil as a component of a chemotherapy regimen for adenocarcinoma of the breast (2.3), gastric adenocarcinoma (2.4), pancreatic adenocarcinoma (2.5)

Pharmacy Bulk

Package: Prepare doses for more than one patient in a Pharmacy Admixture Service under appropriate conditions for cytotoxic drugs. Do not inject entire contents of vial directly into patients. Use within 4 hours of puncture. (2.7, 2.8)

2.1 General Dosage Information Fluorouracil is recommended for administration either as an intravenous bolus or as an intravenous infusion. Do not inject the entire contents of the vial directly into patients. Individualize the dose and dosing schedule of fluorouracil based on tumor type, the specific regimen administered, disease state, response to treatment, and patient risk factors.

2.2 Recommended Dosage for Adenocarcinoma of the Colon and Rectum The recommended dose of fluorouracil, administered in an infusional regimen in combination with leucovorin alone, or in combination with leucovorin and oxaliplatin or irinotecan, is 400 mg/m 2 by intravenous bolus on Day 1, followed by 2400 mg/m 2 to 3000 mg/m 2 intravenously as a continuous infusion over 46 hours every two weeks. The recommended dose of fluorouracil, if administered in a bolus dosing regimen in combination with leucovorin, is 500 mg/m 2 by intravenous bolus on Days 1, 8, 15, 22, 29, and 36 in 8-week cycles.

2.3 Recommended Dosage for Adenocarcinoma of the Breast The recommended dose of fluorouracil, administered as a component of a cyclophosphamide-based multidrug regimen, is 500 mg/m 2 or 600 mg/m 2 intravenously on Days 1 and 8 every 28 days for 6 cycles.

2.4 Recommended Dosage for Gastric Adenocarcinoma The recommended dose of fluorouracil, administered as a component of a platinum-containing multidrug chemotherapy regimen, is 200 mg/m2 to 1000 mg/m2 intravenously as a continuous infusion over 24 hours. The frequency of dosing in each cycle and the length of each cycle will depend on the dose of fluorouracil and the specific regimen administered.

2.5 Recommended Dosage for Pancreatic Adenocarcinoma The recommended dose of fluorouracil, administered as an infusional regimen in combination with leucovorin or as a component of a multidrug chemotherapy regimen that includes leucovorin, is 400 mg/m 2 intravenous bolus on Day 1, followed by 2400 mg/m 2 intravenously as a continuous infusion over 46 hours every two weeks.

2.6 Dose Modifications Withhold fluorouracil for any of the following: Development of angina, myocardial infarction/ischemia, arrhythmia, or heart failure in patients with no history of coronary artery disease or myocardial dysfunction <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2)]</span> Hyperammonemic encephalopathy <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3)]</span> Acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4)]</span>

Grade

3 or 4 diarrhea [see Warnings and Precautions (5.5)]

Grade

2 or 3 palmar-plantar erythrodysesthesia (hand-foot syndrome) [see Warnings and Precautions (5.6)]

Grade

3 or 4 mucositis [see Warnings and Precautions (5.8)]

Grade

4 myelosuppression [see Warnings and Precautions (5.7)] Upon resolution or improvement to Grade 1 diarrhea, mucositis, myelosuppression, or palmar-plantar erythrodysesthesia, resume fluorouracil administration at a reduced dose. There is no recommended dose for resumption of fluorouracil administration following development of any of the following adverse reactions: Cardiac toxicity Hyperammonemic encephalopathy Acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances

2.7 Preparation for Administration Fluorouracil is supplied in a pharmacy bulk package consisting of a vial. The pharmacy bulk package can be used to prepare doses for more than one patient. It is not supplied with a sterile transfer device, which is required for dispensing when multiple doses will be prepared from the single vial.

The

50 mL/100 mL vial is only intended for preparation in a Pharmacy Admixture Service under appropriate conditions for cytotoxic drugs [see References (15)]. Store vial at room temperature. Using aseptic conditions, penetrate the container closure once with a suitable sterile transfer device or dispensing set that allows measured distribution of the contents. Record the date and time the vial was opened on the vial label. Discard the pharmacy bulk package 4 hours after penetration of the container closure. Withdraw the calculated dose for an individual patient into a sterile syringe. Inspect the solution in syringe for particulate matter and discoloration prior to administration or further dilution. Discard syringe if the solution is discolored or contains particulate matter.

2.8 Administration Do not administer in the same intravenous line concomitantly with other medicinal products. For bolus administration, store undiluted fluorouracil in the syringe for up to 4 hours at room temperature (25°C). Administer fluorouracil as an intravenous bolus through an established intravenous line. Store diluted solutions of fluorouracil for up to 4 hours at room temperature (25°C) prior to administration to the patient. For intravenous infusion regimens, administer through a central venous line using an infusion pump.

2.1 General Dosage Information Fluorouracil is recommended for administration either as an intravenous bolus or as an intravenous infusion. Do not inject the entire contents of the vial directly into patients. Individualize the dose and dosing schedule of fluorouracil based on tumor type, the specific regimen administered, disease state, response to treatment, and patient risk factors.

2.2 Recommended Dosage for Adenocarcinoma of the Colon and Rectum The recommended dose of fluorouracil, administered in an infusional regimen in combination with leucovorin alone, or in combination with leucovorin and oxaliplatin or irinotecan, is 400 mg/m 2 by intravenous bolus on Day 1, followed by 2400 mg/m 2 to 3000 mg/m 2 intravenously as a continuous infusion over 46 hours every two weeks. The recommended dose of fluorouracil, if administered in a bolus dosing regimen in combination with leucovorin, is 500 mg/m 2 by intravenous bolus on Days 1, 8, 15, 22, 29, and 36 in 8-week cycles.

2.3 Recommended Dosage for Adenocarcinoma of the Breast The recommended dose of fluorouracil, administered as a component of a cyclophosphamide-based multidrug regimen, is 500 mg/m 2 or 600 mg/m 2 intravenously on Days 1 and 8 every 28 days for 6 cycles.

2.4 Recommended Dosage for Gastric Adenocarcinoma The recommended dose of fluorouracil, administered as a component of a platinum-containing multidrug chemotherapy regimen, is 200 mg/m2 to 1000 mg/m2 intravenously as a continuous infusion over 24 hours. The frequency of dosing in each cycle and the length of each cycle will depend on the dose of fluorouracil and the specific regimen administered.

2.5 Recommended Dosage for Pancreatic Adenocarcinoma The recommended dose of fluorouracil, administered as an infusional regimen in combination with leucovorin or as a component of a multidrug chemotherapy regimen that includes leucovorin, is 400 mg/m 2 intravenous bolus on Day 1, followed by 2400 mg/m 2 intravenously as a continuous infusion over 46 hours every two weeks.

2.6 Dose Modifications Withhold fluorouracil for any of the following: Development of angina, myocardial infarction/ischemia, arrhythmia, or heart failure in patients with no history of coronary artery disease or myocardial dysfunction <span class="opacity-50 text-xs">[see Warnings and Precautions (5.2)]</span> Hyperammonemic encephalopathy <span class="opacity-50 text-xs">[see Warnings and Precautions (5.3)]</span> Acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4)]</span>

Grade

3 or 4 diarrhea [see Warnings and Precautions (5.5)]

Grade

2 or 3 palmar-plantar erythrodysesthesia (hand-foot syndrome) [see Warnings and Precautions (5.6)]

Grade

3 or 4 mucositis [see Warnings and Precautions (5.8)]

Grade

4 myelosuppression [see Warnings and Precautions (5.7)] Upon resolution or improvement to Grade 1 diarrhea, mucositis, myelosuppression, or palmar-plantar erythrodysesthesia, resume fluorouracil administration at a reduced dose. There is no recommended dose for resumption of fluorouracil administration following development of any of the following adverse reactions: Cardiac toxicity Hyperammonemic encephalopathy Acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances

2.7 Preparation for Administration Fluorouracil is supplied in a pharmacy bulk package consisting of a vial. The pharmacy bulk package can be used to prepare doses for more than one patient. It is not supplied with a sterile transfer device, which is required for dispensing when multiple doses will be prepared from the single vial.

The

50 mL/100 mL vial is only intended for preparation in a Pharmacy Admixture Service under appropriate conditions for cytotoxic drugs [see References (15)]. Store vial at room temperature. Using aseptic conditions, penetrate the container closure once with a suitable sterile transfer device or dispensing set that allows measured distribution of the contents. Record the date and time the vial was opened on the vial label. Discard the pharmacy bulk package 4 hours after penetration of the container closure. Withdraw the calculated dose for an individual patient into a sterile syringe. Inspect the solution in syringe for particulate matter and discoloration prior to administration or further dilution. Discard syringe if the solution is discolored or contains particulate matter.

2.8 Administration Do not administer in the same intravenous line concomitantly with other medicinal products. For bolus administration, store undiluted fluorouracil in the syringe for up to 4 hours at room temperature (25°C). Administer fluorouracil as an intravenous bolus through an established intravenous line. Store diluted solutions of fluorouracil for up to 4 hours at room temperature (25°C) prior to administration to the patient. For intravenous infusion regimens, administer through a central venous line using an infusion pump.

CONTRAINDICATIONS Fluorouracil 5% Topical Cream may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women with either the topical or the parenteral forms of fluorouracil. One birth defect (cleft lip and palate) has been reported in the newborn of a patient using Fluorouracil 5% Topical Cream as recommended. One birth defect (ventricular septal defect) and cases of miscarriage have been reported when Fluorouracil 5% Topical Cream was applied to mucous membrane areas. Multiple birth defects have been reported in a fetus of a patient treated with intravenous fluorouracil. Animal reproduction studies have not been conducted with Fluorouracil 5% Topical Cream. Fluorouracil administered parenterally has been shown to be teratogenic in mice, rats, and hamsters when given at doses equivalent to the usual human intravenous dose; however, the amount of fluorouracil absorbed systemically after topical administration to actinic keratoses is minimal (see CLINICAL PHARMACOLOGY ). Fluorouracil exhibited maximum teratogenicity when given to mice as single intraperitoneal injections of 10 to 40 mg/kg on Day 10 or 12 of gestation. Similarly, intraperitoneal doses of 12 to 37 mg/kg given to rats between Days 9 and 12 of gestation and intramuscular doses of 3 to 9 mg/kg given to hamsters between Days 8 and 11 of gestation were teratogenic and/or embryotoxic (i.e., resulted in increased resorptions or embryolethality). In monkeys, divided doses of 40 mg/kg given between Days 20 and 24 of gestation were not teratogenic. Doses higher than 40 mg/kg resulted in abortion.

Fluorouracil

5% Topical Cream should not be used in patients with dihydropyrimidine dehydrogenase (DPD) enzyme deficiency. A large percentage of fluorouracil is catabolized by the DPD enzyme. DPD enzyme deficiency can result in shunting of fluorouracil to the anabolic pathway, leading to cytotoxic activity and potential toxicities.

Fluorouracil

5% Topical Cream is contraindicated in women who are or may become pregnant during therapy. If this drug is used during pregnancy, or if the patient becomes pregnant while using this drug, the patient should be apprised of the potential hazard to the fetus.

Fluorouracil

5% Topical Cream is also contraindicated in patients with known hypersensitivity to any of its components.

REACTIONS The following serious adverse reactions are discussed in more detail in other sections of the labeling: Application Site Adverse Reactions [see Warnings and Precautions (5.1) ]

Hypersensitivity

Reactions [see Warnings and Precautions (5.2) ]

Ophthalmic Adverse

Reactions [see Warnings and Precautions (5.3) ] Photosensitivity [see Warnings and Precautions (5.4) ] Embryofetal toxicity [see Warnings and Precautions (5.5) ] Toxicity in Patients with Dihydropyrimidine Dehydrogenase Deficiency [see Warnings and Precautions (5.6) ] The most common (incidence > 68%) adverse reactions occur at the application site and include erythema, scaling/dryness, crusting, pruritus, stinging/burning, edema, and erosions. Erythema is observed in 99% of patients with actinic keratosis treated with Tolak Cream ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Hill Dermaceuticals at 1-800-344-5707 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to Tolak Cream in 397 subjects with actinic keratosis in vehicle-controlled trials. The population ranged in age from 33 to 94 years, was 80% male, and almost all were Caucasian. Most subjects were treated with Tolak Cream once daily for 4 weeks. Throughout the 4-week treatment and the 4-week post-treatment periods, the trials specifically monitored for adverse reactions related to tolerability, including erythema, scaling/dryness, edema, crusting, erosions, stinging/burning, and pruritus. The number and percentage of subjects with each of these monitored adverse reactions at one or more post-baseline visit(s) during the clinical trials are shown in Table 1.

Table

1: Incidence of Application Site Adverse Reactions Occurring with 4 Weeks of Tolak Cream Treatment in Clinical Trials 1 and 2 Tolak Cream N=397 n (%) Vehicle N=120 n (%) Mild, Moderate or Severe Severe Only Mild, Moderate or Severe Severe Only Erythema 394 (99%) 174 (44%) 102 (85%) 0 (0%) Scaling/ Dryness 377 (95%) 94 (24%) 99 (83%) 0 (0%)

Crusting

346 (87%) 87 (22%) 46 (38%) 0 (0%)

Pruritus

337 (85%) 65 (16%) 46 (38%) 1 (1%) Stinging/ Burning 346 (87%) 101 (25%) 42 (35%) 0 (0%)

Edema

275 (69%) 30 (8%) 11 (9%) 0 (0%)

Erosions

271 (68%) 44 (11%) 14 (12%) 0 (0%) In these clinical trials, the intensity of the adverse reactions in subjects using Tolak Cream generally increased over the 4-week treatment period, usually reaching maximal levels at 4 weeks of treatment and then diminishing to baseline levels within 4 weeks after cessation of treatment.

In Trials

1 and 2, 11% of Tolak Cream-treated and 3% of vehicle-treated subjects discontinued treatment because of adverse reactions. Of these subjects, the majority had adverse reactions at the application site. Eye swelling, leading to discontinuation, occurred in one subject with Tolak Cream use .

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of topical fluorouracil. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders : leukocytosis, pancytopenia, thrombocytopenia, eosinophilia, neutrophil toxic granulation Eye disorders : corneal disorder, conjunctival disorder, eye irritation, conjunctivitis, lacrimation Gastrointestinal disorders : stomatitis General Disorders and Administration Site Conditions : medicinal taste Infections and Infestations : herpes simplex Neoplasms : chronic lymphocytic leukemia, non-melanoma skin cancer Nervous system disorders : insomnia, irritability Psychiatric disorders : emotional distress Skin and subcutaneous tissue disorders : blistering, allergic contact dermatitis, photosensitivity, pain, scarring, skin irritation, rash, ulceration, hyperpigmentation, alopecia, bullous pemphigoid, ichthyosis, suppuration, swelling, soreness, telangiectasia, tenderness, urticaria

AND PRECAUTIONS

• Increased Risk of Serious or Fatal Adverse Reactions in Patients with Low or Absent Dipyrimidine Dehydrogenase Activity: Withhold or permanently discontinue fluorouracil in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of dipyrimidine dehydrogenase (DPD) activity. No fluorouracil dose has been proven safe in patients with absent DPD activity. ( 5.1 )
• Cardiotoxicity: Fluorouracil can cause cardiotoxicity, including angina, myocardial infarction/ischemia, arrhythmia, and heart failure. Withhold fluorouracil for cardiac toxicity. ( 5.2 )
• Hyperammonemic Encephalopathy: Altered mental status, confusion, disorientation, coma, or ataxia with elevated serum ammonia level can occur within 72 hours of initiation of fluorouracil. Withhold fluorouracil and initiate ammonia-lowering therapy. ( 5.3 )
• Neurologic Toxicity: Fluorouracil can cause acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances. Withhold fluorouracil for neurologic toxicity. ( 5.4 )
• Diarrhea: Fluorouracil can cause severe diarrhea. Withhold fluorouracil for severe diarrhea until resolved. ( 5.5 )
• Palmar-Plantar Erythrodysesthesia (Hand-Foot Syndrome): Fluorouracil can cause hand-foot syndrome. If severe, discontinue fluorouracil until resolved or decreased to Grade 1, then resume at a reduced dose. ( 5.6 )
• Myelosuppression: Fluorouracil can cause severe and fatal myelosuppression. Withhold fluorouracil until severe myelosuppression resolves, then resume at a reduced dose. ( 5.7)
• Mucositis: Fluorouracil can cause severe mucositis. Discontinue fluorouracil until resolved or decreased to Grade 1, then resume at a reduced dose. ( 5.8 )
• Increased Risk of Elevated INR with Warfarin: Concurrent administration with warfarin can result in clinically significant increases in coagulation parameters: Closely monitor INR and prothrombin time. ( 5.9 )
• Embryofetal Toxicity: Fluorouracil can cause fetal harm. Advise females and males of reproductive potential of the potential risk to a fetus. ( 5.10 , 8.1 , 8.6 )

5.1 Increased Risk of Serious or Fatal Adverse Reactions in Patients with Low or Absent Dipyrimidine Dehydrogenase (DPD)

Activity

Based on postmarketing reports, patients with certain homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near complete absence of DPD activity are at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by fluorouracil (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by fluorouracil. Withhold or permanently discontinue fluorouracil based on clinical assessment of the onset, duration and severity of the observed toxicities in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No fluorouracil dose has been proven safe for patients with complete absence of DPD activity. There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test.

5.2 Cardiotoxicity Fluorouracil can cause cardiotoxicity, including angina, myocardial infarction/ischemia, arrhythmia, and heart failure, based on postmarketing reports. Reported risk factors for cardiotoxicity are administration by continuous infusion rather than intravenous bolus and presence of coronary artery disease. Withhold fluorouracil for cardiotoxicity. The risks of resumption of fluorouracil in patients with cardiotoxicity that has resolved have not been established.

5.3 Hyperammonemic Encephalopathy Fluorouracil can cause hyperammonemic encephalopathy in the absence of liver disease or other identifiable cause, based on postmarketing reports. Signs or symptoms of hyperammonemic encephalopathy began within 72 hours after initiation of fluorouracil infusion; these included altered mental status, confusion, disorientation, coma, or ataxia, in the presence of concomitant elevated serum ammonia level. Withhold fluorouracil for hyperammonemic encephalopathy and initiate ammonia-lowering therapy. The risks of resumption of fluorouracil in patients with hyperammonemic encephalopathy that has resolved have not been established.

5.4 Neurologic Toxicity Fluorouracil can cause neurologic toxicity, including acute cerebellar syndrome and other neurologic events, based on postmarketing reports. Neurologic symptoms included confusion, disorientation, ataxia, or visual disturbances. Withhold fluorouracil for neurologic toxicity. There are insufficient data on the risks of resumption of fluorouracil in patients with neurologic toxicity that has resolved.

5.5 Diarrhea Fluorouracil can cause severe diarrhea. Withhold fluorouracil for Grade 3 or 4 diarrhea until resolved or decreased in intensity to Grade 1, then resume fluorouracil at a reduced dose. Administer fluids, electrolyte replacement, or antidiarrheal treatments as necessary.

5.6 Palmar-Plantar Erythrodysesthesia (Hand-Foot Syndrome) Fluorouracil can cause palmar-plantar erythrodysesthesia, also known as hand-foot syndrome (HFS). Symptoms of HFS include a tingling sensation, pain, swelling, and erythema with tenderness, and desquamation. HFS occurs more commonly when fluorouracil is administered as a continuous infusion than when fluorouracil is administered as a bolus injection, and has been reported to occur more frequently in patients with previous exposure to chemotherapy. HFS is generally observed after 8-9 weeks of fluorouracil administration but may occur earlier. Institute supportive measures for symptomatic relief of HFS. Withhold fluorouracil administration for Grade 2 or 3 HFS; resume fluorouracil at a reduced dose when HFS is completely resolved or decreased in severity to Grade 1.

5.7 Myelosuppression Fluorouracil can cause severe and fatal myelosuppression which may include neutropenia, thrombocytopenia, and anemia. The nadir in neutrophil counts commonly occurs between 9 and 14 days after fluorouracil administration. Obtain complete blood counts prior to each treatment cycle, weekly if administered on a weekly or similar schedule, and as needed. Withhold fluorouracil until Grade 4 myelosuppression resolves; resume fluorouracil at a reduced dose when myelosuppression has resolved or improved to Grade 1 in severity.

5.8 Mucositis Mucositis, stomatitis or esophagopharyngitis, which may lead to mucosal sloughing or ulceration, can occur with fluorouracil. The incidence is reported to be higher with administration of fluorouracil by intravenous bolus compared with administration by continuous infusion. Withhold fluorouracil administration for Grade 3 or 4 mucositis; resume fluorouracil at a reduced dose once mucositis has resolved or decreased in severity to Grade 1.

5.9 Increased Risk of Elevated International Normalized Ratio (INR) with Warfarin Clinically significant elevations in coagulation parameters have been reported during concomitant use of warfarin and fluorouracil. Closely monitor patients receiving concomitant coumarin-derivative anticoagulants such as warfarin for INR or prothrombin time in order to adjust the anticoagulant dose accordingly <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span> .

5.10 Embryofetal Toxicity Based on its mechanism of action, f luorouracil can cause fetal harm when administered to a pregnant woman. In animal studies, administration of fluorouracil at doses lower than a human dose of 12 mg/kg caused teratogenicity. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during and for 3 months following cessation of therapy with fluorouracil <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.6) , Clinical Pharmacology ( 12.1 ) , and Nonclinical Toxicology ( 13.1) ]</span>.

5.1 Increased Risk of Serious or Fatal Adverse Reactions in Patients with Low or Absent Dipyrimidine Dehydrogenase (DPD)

Activity

Based on postmarketing reports, patients with certain homozygous or certain compound heterozygous mutations in the DPD gene that result in complete or near complete absence of DPD activity are at increased risk for acute early-onset of toxicity and severe, life-threatening, or fatal adverse reactions caused by fluorouracil (e.g., mucositis, diarrhea, neutropenia, and neurotoxicity). Patients with partial DPD activity may also have increased risk of severe, life-threatening, or fatal adverse reactions caused by fluorouracil. Withhold or permanently discontinue fluorouracil based on clinical assessment of the onset, duration and severity of the observed toxicities in patients with evidence of acute early-onset or unusually severe toxicity, which may indicate near complete or total absence of DPD activity. No fluorouracil dose has been proven safe for patients with complete absence of DPD activity. There is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test.

5.2 Cardiotoxicity Fluorouracil can cause cardiotoxicity, including angina, myocardial infarction/ischemia, arrhythmia, and heart failure, based on postmarketing reports. Reported risk factors for cardiotoxicity are administration by continuous infusion rather than intravenous bolus and presence of coronary artery disease. Withhold fluorouracil for cardiotoxicity. The risks of resumption of fluorouracil in patients with cardiotoxicity that has resolved have not been established.

5.3 Hyperammonemic Encephalopathy Fluorouracil can cause hyperammonemic encephalopathy in the absence of liver disease or other identifiable cause, based on postmarketing reports. Signs or symptoms of hyperammonemic encephalopathy began within 72 hours after initiation of fluorouracil infusion; these included altered mental status, confusion, disorientation, coma, or ataxia, in the presence of concomitant elevated serum ammonia level. Withhold fluorouracil for hyperammonemic encephalopathy and initiate ammonia-lowering therapy. The risks of resumption of fluorouracil in patients with hyperammonemic encephalopathy that has resolved have not been established.

5.4 Neurologic Toxicity Fluorouracil can cause neurologic toxicity, including acute cerebellar syndrome and other neurologic events, based on postmarketing reports. Neurologic symptoms included confusion, disorientation, ataxia, or visual disturbances. Withhold fluorouracil for neurologic toxicity. There are insufficient data on the risks of resumption of fluorouracil in patients with neurologic toxicity that has resolved.

5.5 Diarrhea Fluorouracil can cause severe diarrhea. Withhold fluorouracil for Grade 3 or 4 diarrhea until resolved or decreased in intensity to Grade 1, then resume fluorouracil at a reduced dose. Administer fluids, electrolyte replacement, or antidiarrheal treatments as necessary.

5.6 Palmar-Plantar Erythrodysesthesia (Hand-Foot Syndrome) Fluorouracil can cause palmar-plantar erythrodysesthesia, also known as hand-foot syndrome (HFS). Symptoms of HFS include a tingling sensation, pain, swelling, and erythema with tenderness, and desquamation. HFS occurs more commonly when fluorouracil is administered as a continuous infusion than when fluorouracil is administered as a bolus injection, and has been reported to occur more frequently in patients with previous exposure to chemotherapy. HFS is generally observed after 8-9 weeks of fluorouracil administration but may occur earlier. Institute supportive measures for symptomatic relief of HFS. Withhold fluorouracil administration for Grade 2 or 3 HFS; resume fluorouracil at a reduced dose when HFS is completely resolved or decreased in severity to Grade 1.

5.7 Myelosuppression Fluorouracil can cause severe and fatal myelosuppression which may include neutropenia, thrombocytopenia, and anemia. The nadir in neutrophil counts commonly occurs between 9 and 14 days after fluorouracil administration. Obtain complete blood counts prior to each treatment cycle, weekly if administered on a weekly or similar schedule, and as needed. Withhold fluorouracil until Grade 4 myelosuppression resolves; resume fluorouracil at a reduced dose when myelosuppression has resolved or improved to Grade 1 in severity.

5.8 Mucositis Mucositis, stomatitis or esophagopharyngitis, which may lead to mucosal sloughing or ulceration, can occur with fluorouracil. The incidence is reported to be higher with administration of fluorouracil by intravenous bolus compared with administration by continuous infusion. Withhold fluorouracil administration for Grade 3 or 4 mucositis; resume fluorouracil at a reduced dose once mucositis has resolved or decreased in severity to Grade 1.

5.9 Increased Risk of Elevated International Normalized Ratio (INR) with Warfarin Clinically significant elevations in coagulation parameters have been reported during concomitant use of warfarin and fluorouracil. Closely monitor patients receiving concomitant coumarin-derivative anticoagulants such as warfarin for INR or prothrombin time in order to adjust the anticoagulant dose accordingly <span class="opacity-50 text-xs">[see Drug Interactions ( 7 )]</span> .

5.10 Embryofetal Toxicity Based on its mechanism of action, f luorouracil can cause fetal harm when administered to a pregnant woman. In animal studies, administration of fluorouracil at doses lower than a human dose of 12 mg/kg caused teratogenicity. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during and for 3 months following cessation of therapy with fluorouracil <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.6) , Clinical Pharmacology ( 12.1 ) , and Nonclinical Toxicology ( 13.1) ]</span>.

PRECAUTIONS General There is a possibility of increased absorption through ulcerated or inflamed skin. Information for the Patient Patients using fluorouracil cream, 0.5% should receive the following information and instructions: 1. This medication is to be used as directed. 2. This medication should not be used for any disorder other than that for which it was prescribed. 3. It is for topical use only. 4. Avoid contact with the eyes, eyelids, nostrils, and mouth. 5. Cleanse affected area and wait 10 minutes before applying fluorouracil cream, 0.5%. 6. Wash hands immediately after applying fluorouracil cream, 0.5%. 7. Avoid prolonged exposure to sunlight or other forms of ultraviolet irradiation during treatment, as the intensity of the reaction may be increased. 8. Most patients using fluorouracil cream, 0.5% get skin reactions where the medicine is used. These reactions include redness, dryness, burning, pain, erosion (loss of the upper layer of skin), and swelling. Irritation at the application site may persist for two or more weeks after therapy is discontinued. Treated areas may be unsightly during and after therapy. 9. If you develop abdominal pain, bloody diarrhea, vomiting, fever, or chills while on fluorouracil cream, 0.5% therapy, stop the medication and contact your physician and/or pharmacist. 10. Report any side effects to the physician and/or pharmacist. 11. Fluorouracil, including fluorouracil cream, 0.5% may be fatal if ingested by pets. Avoid allowing pets to contact the fluorouracil cream, 0.5% container or the skin where fluorouracil cream, 0.5% has been applied. Store fluorouracil cream, 0.5% out of reach of pets. Safely discard or clean any cloth or applicator that may retain fluorouracil cream, 0.5% and avoid leaving any residues of fluorouracil cream, 0.5% on your hands, clothing, carpeting or furniture.

Laboratory

Tests To rule out the presence of a frank neoplasm, a biopsy may be considered for those areas failing to respond to treatment or recurring after treatment. Carcinogenesis, Mutagenesis, Impairment of Fertility Adequate long-term studies in animals to evaluate carcinogenic potential have not been conducted with fluorouracil. Studies with the active ingredient of fluorouracil cream, 0.5%, fluorouracil, have shown positive effects in in vitro and in vivo tests for mutagenicity and on impairment of fertility in in vivo animal studies. Fluorouracil produced morphological transformation of cells in in vitro cell transformation assays. Morphological transformation was also produced in an in vitro assay by a metabolite of fluorouracil, and the transformed cells produced malignant tumors when injected into immunosuppressed syngeneic mice. Fluorouracil has been shown to exert mutagenic activity in yeast cells, Bacillus subtilis, and Drosophila assays. In addition, fluorouracil has produced chromosome damage at concentrations of 1.0 and 2.0 mcg/mL in an in vitro hamster fibroblast assay, was positive in a microwell mouse lymphoma assay, and was positive in in vivo micronucleus assays in rats and mice following intraperitoneal administration. Some patients receiving cumulative doses of 0.24 to 1.0 g of fluorouracil parenterally have shown an increase in numerical and structural chromosome aberrations in peripheral blood lymphocytes. Fluorouracil has been shown to impair fertility after parenteral administration in rats. Fluorouracil administered at intraperitoneal doses of 125 and 250 mg/kg has been shown to induce chromosomal aberrations and changes in chromosome organization of spermatogonia in rats. In mice, single-dose intravenous and intraperitoneal injections of fluorouracil have been reported to kill differentiated spermatogonia and spermatocytes at a dose of 500 mg/kg and produce abnormalities in spermatids at 50 mg/kg.

Pediatric Use

Actinic keratosis is not a condition seen within the pediatric population, except in association with rare genetic diseases. Fluorouracil cream, 0.5% should not be used in children. The safety and effectiveness of fluorouracil cream, 0.5% have not been established in patients less than 18 years old.

Geriatric

Use No significant differences in safety and efficacy measures were demonstrated in patients age 65 and older compared to all other patients.

Pregnancy

See CONTRAINDICATIONS.

Nursing

Women It is not known whether fluorouracil is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from fluorouracil, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

INTERACTIONS 7.1. Anticoagulants and CYP 2C9 Substrates Elevated coagulation times have been reported in patients taking fluorouracil concomitantly with warfarin. While pharmacokinetic data are not available to assess the effect of fluorouracil administration on warfarin pharmacokinetics, the elevation of coagulation times that occurs with the fluorouracil prodrug capecitabine is accompanied by an increase in warfarin concentrations. Thus, the interaction may be due to inhibition of cytochrome P450 2C9 by fluorouracil or its metabolites.